With over 30 years of experience formulating both large and small molecules for injection, you can rely on Curia. We can identify the quality attributes that impact the clinical performance and safety of formulations, analyze the manufacturability of dosage forms, and assess stability in primary packaging.
Pre-formulation characterization studies generally include accelerated stability (stress) studies, stability-indicating analytical method development, and other physiochemical characterizations designed to pinpoint potential product candidate stability problems and enable formulation optimization.
- Understand the significant physicochemical properties
- Estimate a product’s stability when exposed to various common stresses
- Develop stability-indicating assays for major degradation products
- Decide upon a lyophilized or liquid formulation for initial clinical studies
- Finalize a formulation development research protocol (matrix of buffer, pH, stabilizer, tonicity modifier; analytical methods; etc.)
Curia offers a wide variety of services to help formulate your drug product:
- Analytical Method Capabilities
- Formulation Development
- Lyophilization Cycle Development
- In Use, Compatibility, and Robustness
- Technology & Innovation
- Modalities and Stability Studies
Utilizing specialized technology, our skilled experts can develop liquid, lyophilized, or frozen dosage forms, where there is sufficient solubility and stability with the target drug substance.
We offer aseptic fill/finish services, including aseptic lyophilization for both clinical trials and commercial manufacturing.
Sufficient stability information is required to achieve liquid formulations as most biopharmaceuticals have limited stability in liquid state. It is also important to understand that product stability in prefilled syringe may be different from the same formulation filled in vials.
If improved product stability is required, lyophilization typically comes into play. To achieve robust lyophilized formulations, additional formulation factors listed below need to be considered above and beyond storage stability.
- Lyophilization cycle optimization
- Elegant appearance of the lyophilized cake
- Good stability during the freeze-drying process.
- Easy, rapid, and thorough reconstitution
Appropriate for clients wanting to quickly determine if their compound is safe and effective in early (Phase I) clinical trials.
Combining two products in one formulation, e.g., co-formulation, is used when multi-dosing from a single vial is beneficial. In general, the addition of preservative(s), regardless of the type and amount utilized, significantly changes the stability profiles of proteins. In some extreme cases, visible precipitation and aggregation have been reported from the introduction of these materials. Therefore, the effect of various preservatives on the stability of protein should be carefully examined. Other experiments are also required to qualify a protein product for multi-dose formulation capabilities. The most notable tests include analyses for antimicrobial preservative effectiveness and stopper resealing. As proteins have limited stability in the presence of preservatives, dual chamber syringes or dual chamber cartridges containing bacteriostatic diluents are routinely used.
We measure the secondary, tertiary, and quaternary structure of biologically active proteins. This includes:
- Fourier Transformed Infrared Spectroscopy (FTIR)
- Differential Scanning Calorimetry (DSC)
- Fluorescence Spectroscopy
We monitor various degradation of biological therapeutics, including:
- Ion-exchange (cation-exchange, anion-exchange)
- Reversed Phase
- Hydrophobic Interaction
- Various detectors: UV, Fluorescence, reflective index, evaporative light scattering, charged aerosol
This method separates impurities based on both charge and mass, such as:
- Capillary Electrophoresis (CE)
- Sodium dodecyl sulfate electrophoresis (SDS-PAGE)
Measurement for manufacturing process as well as injection through narrow bore needles.
Subvisible Particle Analysis
The potential immunogenicity of particles ranging from nanometer to micron sizes in biotherapeutics has been a growing area of discussion between regulators and industry. Both the USP and Ph.Eur. currently require biopharmaceutical products to quantify subvisible particles larger than 10 µm and 25 µm, respectively.
Due to the complex milieu of subvisible particles, sample preparation and the method of analysis can affect the accuracy of:
- Particle Sizing
- Particle Counting
- Particle Classification
Consequently, multiple orthogonal techniques are strongly recommended for subvisible particle analysis. We offer multiple orthogonal techniques for subvisible particle characterization:
- Flow Imaging Microscopy (MFI and Flowcam)
- Dynamic Light scattering (Zetasizer, Wyatt)
- HIAC Liquid Particle Counter
- Light Obscuration
Other useful analytical methods include:
- Sub-ambient differential scanning calorimetry (characterization of frozen formulations)
- Imaged capillary isoelectric focusing (iCIEF)
- Karl Fisher
In order for us to develop the ideal lyophilization process, we must understand the following regarding your project:
- Product integrity during lyophilization: stability indicating assays, FTIR structural analysis
- Physical properties of formulations under frozen condition, e.g., glass transition temperature or collapse temperature, re-crystallization or devitrification, and eutectic melting temperature of excipient in the unfrozen fraction
- Presence of key stabilizers, e.g., surfactant, water-replacing glass formers
- Potential pH changes during freezing due to selective crystallization of buffer components
- Phase separation of key ingredients during freezing
- Desired final moisture content
- Vapor pressure of ice at desired product temperature
Having an inefficient biologic development process can have significant consequences in later clinical and commercial stages. Poor product quality and higher than expected costs can create havoc on a drug development program. Recognizing that every biologic drug product is unique, we take a customized approach when it comes to developing process development. During process development, we identify and optimize process conditions and parameters.
The following are just some of the areas we concentrate on:
- Sterile filtration
- Buffer characterization
- Aseptic fill/finish process development
- Temperature sensitive formulations
- Process scale up
- Engineering runs
Formulation Robustness Study
After a formulation matrix is identified, the stability of the drug product within the specification of each formulation parameter needs to be generated. In addition, the effect of various excursions from controlled stability study conditions on product stability have to be studied.
Examples of robustness studies include:
- Formulation robustness study
- Transportation study
- Process excursion study
- Temperature excursion study
In-use Stability Studies
The stability of the drug product during intended application processes should be investigated, such as withdrawal from the primary container closure system, expulsion through delivery devices, mixing with diluents, adjuvants, etc.
Examples of In-use Stability Study include:
- Administration with disposable syringes
- Administration with IV catheter with or without in-line filter
- Dilution with IV infusion bag
- Stability and integrity of multidose formulation over multiple entry
Since a drug product comes in contact with other materials, molecules, etc., the drug product’s stability and integrity needs to be demonstrated.
Examples of compatibility studies include:
- Prefilled syringe compatibility study
- Extractables and leachables study
- Secondary container/closure systems
- Excipient-drug compatibility
- Drug-drug compatibility study
The ease of a prefilled syringe with the stability of a lyophilized drug in a one-step reconstitution and injection.
The Lyotip Advantage
- User-friendly design favored by patients and/or practitioners
- Eliminates need for separate mixing steps
- Designed for use with existing fill/finish and lyophilized process
- May permit decreased use of cold chain handling
- Cost effective, highly valued differentiation for SC and IV lyophilized drugs
Lyotip was chosen as “Best” in ease of use, preparation speed, learning ease, portability and economy in a third-party market study of competitors.
Concentrating and efficiently delivering high-dose biologic medicine.
The Excelse Advantage
Our groundbreaking Excelse high-concentration formulation technology uses customized blends of amino acids to highly stabilize and concentrate delicate biotechnology medicines.
- Permits concentration of intravenous liquid and lyophilized biologics into liquid subcutaneous injections
- Significantly reduces viscosity
- Allows for concentrations of up 300 mg/mL allowing 1 mL injections
- Uses stabilizers that are non-active and FDA approved
We have experience with various biological and small molecule drug products such as:
- Viral Particles
- Plasmid DNA
- Lipid nano particles
- Small molecules
Regulators require stability studies to show that your drug product is safe and effective during its shelf life. While accelerated stability studies are useful for predicting potential degradation products and appropriate analytical methods, they are not sufficient for regulatory approval. We have wide ranging experience in performing both accelerated and real-time stability studies.